The present invention relates to methods for treating and/or preventing tissue and cell damage caused by reactive oxygen species in mammals. More specifically, the present invention relates to the prevention and/or reduction of tissue and cell damage through the administration of histamine and histamine agonists.
The complete reduction of one molecule of O.sub.2 to water is a four-electron process. Oxidative metabolism continually generates partially reduced species of oxygen, which are far more reactive, and hence more toxic than O.sub.2 itself. A one-electron reduction of O.sub.2 yields superoxide ion (O.sub.2.sup.-); reduction by an additional electron yields hydrogen peroxide (H.sub.2 O.sub.2), and reduction by a third electron yields a hydroxyl radical (OH.), and a hydroxide ion. Nitrous oxide (NO), is another interesting reactive oxygen metabolite, produced through an alternative pathway. Hydroxyl radicals in particular are extremely reactive and represent the most active mutagen derived from ionizing radiation. All of these species are generated and must be converted to less reactive species if the organism is to survive.
Particular cells of the immune system have harnessed the toxic effects of ROMs as an effector mechanism. Professional phagocytes, polymorphonuclear leukocytes (neutrophils, PMN), monocytes, macrophages, and eosinophils function to protect the host in which they reside from infection by seeking out and destroying invading microbes. These phagocytic cells possess a membrane-bound enzyme system which can be activated to produce toxic oxygen radicals in response to a wide variety of stimuli.
The "increased respiration of phagocytosis" (the respiratory burst) was reported and thought to be a result of increased mitochondrial activity providing additional energy for the processes of phagocytosis. It was later shown that a non-mitochondrial enzymatic system produced the increased levels of oxygen metabolites since the respiratory burst continued even in the presence of mitochondrial inhibitors such as cyanide and antimycin A. In 1968, Paul and Sbarra showed clearly that hydrogen peroxide was produced by stimulated phagocytes and in 1973 Babior and co-workers established that superoxide was a major product of the oxidase. (Paul and Sbarra, Biochim Biophys Acta 156(1):168-78 (1968); Babior, et al., J Clin Invest 52(3):741-4 (1973). It is now generally accepted that the enzyme is membrane bound, exhibits a preference for NADPH (K.sub.m =45 .mu.M over NADH (K.sub.m =450 .mu.M), and converts oxygen to its one electron-reduced product, superoxide. EQU NADPH+H.sup.+ +2O.sub.2.fwdarw.NADP.sup.+ +2H.sup.+ +2O.sub.2.sup.-
The hydrogen peroxide arises from subsequent dismutation of the superoxide. EQU 2O.sub.2.sup.- +2H.sup.+.fwdarw.H.sub.2 O.sub.2 +O.sub.2.sup.-
The enzyme activity is almost undetectable in resting (unstimulated) phagocytes, but increases dramatically upon stimulation. In patients with the rare genetic disorder chronic granulomatous disease (CGD), there is a severe predisposition to chronic recurrent infection. The neutrophils from these patients phagocytose normally but the respiratory burst is absent and NADPH oxidase activity (and radical production) is undetectable, indicating that the oxidase and its product, the reactive oxygen metabolites, have an important bactericidal function.
Neutrophils and macrophages produce oxidizing agents to break through the protective coats or other factors that protect phagocytosed bacteria. The large quantities of superoxide, hydrogen peroxide, and hydroxyl ions are all lethal to most bacteria, even when found in very small quantities.
While there are beneficial effects of these oxygen metabolites, it is clear that inappropriate production of oxygen metabolites can result in severely deleterious effects. Several disease states illustrate this point, including various inflammatory diseases, including rheumatoid arthritis, Crohn's disease, and Adult Respiratory Distress Syndrome (ARDS). An effective method to reduce and/or minimize the production and release of ROMs in patients suffering from a variety of disparate diseases would be a great boon to medicine and service to reduce and eliminate a substantial amount of human suffering.